CANCER SURGERY

Cancer Surgery as a cause of Metastasis

The section you are about to read is earth-shattering. It provides overwhelming and compelling evidence confirming that surgery itself is a significant cause of cancer metastasis.

You would think that cancer surgeons would figure this out themselves. After all, everything discussed here is just a fraction of what is published in the peer-reviewed scientific literature. Sadly, the assembly-line mentality of conventional doctors too often results in these important decisions being overlooked.

Our latest work suggests that transient systemic inflammation resulting from the primary surgery is a main factor in this process.

The surgical removal of a primary tumor has been the cornerstone of treatment for most types of cancer. The rationale for this approach is straightforward– if you can get rid of the cancer by removing it from the body, then a cure can likely be achieved right? The notion that surgical removal of cancerous masses can enhance the risk of tumor recurrence was already acknowledged by the ancient Greeks, who cautioned against disturbing tumors. This was reiterated by Halsted in the beginning of the 20th century. (Halsted 1907)

The surgical approach to cancer does not adequately address the fact that a primary tumor usually suppresses the formation of secondary tumors. Following surgery, the cancer will frequently metastasize, which is to spread to different organs (Krokowski 1979; van der Bij 2009; Ben Eliyahus 1999; Koda 1997; Peng 2006; Horia 2007; Hogan 2011). Quite often the metastatic recurrence is far more serious than the original tumor. In fact, for many cancers it is the metastatic recurrence, and not the primary tumor that ultimately proves to be fatal (Bird 2006).

Even though this contradicts “conventional” medical thinking, the facts are undeniable. A significant number of cancers carry a poor prognosis even after “curative” removal of early stage tumors. (Wikman 2008; Hogan 2011)

To gain a better understanding of how surgery can increase the risk of metastasis, let’s first discuss the actual process of cancer metastasis.

A complicated sequence of events must occur in order for cancer to metastasize (van der Bij 2009). Isolated cancer cells that break away from the primary tumor must first breach the connective tissue immediately surrounding the cancer. Once the cancer cell has broken free of the surrounding connective tissue, the cancer cell enters a blood or lymphatic vessel. This is easier said than done, as entry into a blood vessel requires the cancer cell to secrete enzymes that degrade the basement membrane of the blood vessel (Wagennar-Miller 2004). Entry into a blood vessel is vitally important for the aspiring metastatic cancer cell, since it uses the bloodstream as a highway for transportation to other vital organs of the body—such as the liver, brain, or lungs—where it can form a new deadly tumor

Now that the lone cancer cell has finally entered the bloodstream, its problems have only just begun. Traveling within the bloodstream can be a hazardous journey for cancer cells. Turbulence from the fast moving blood can damage and destroy the cancer cell. Furthermore, cancer cells must avoid detection and destruction from white blood cells circulating in the blood stream

To complete its voyage, the rogue cancer cell must adhere to the lining of the blood vessel, where it degrades through and exits the basement membrane of the blood vessel. Its final task is to burrow through the surrounding connective tissue to arrive at the organ that is its final destination. Now the cancer cell can multiply and form a growing colony that serves as the foundation for a new metastatic cancer. Time is working against these solitary cancer cells. This entire sequence of events must happen quickly, since these cells have a limited life span (Meng et al 2004)

We now see that cancer metastasis is a complicated and difficult process. Fraught with peril, very few free-standing cancer cells survive this arduous journey (van der Bij 2009). The probability of cancer cells surviving this odyssey and forming new metastases can be increased by anything that serves to make this process easier. For example, chronic inflammation will distract the immune system and allow cancer cells to increasingly go unnoticed (Ben-Eliyahu 2003).

In 2 groundbreaking studies published in the medical journals Annals of Surgery in 2009, and Cancers in 2010, researchers reported that cancer surgery itself creates an environment in the body that greatly lessens the obstacles to metastasis that cancers cells must normally face. (van der Bij 2009) (Retsky et al. 2010). Cancer surgery can produce an alternate route of metastasis that bypasses natural barriers. During cancer surgery, the manipulation and removal of the tumor almost always disrupt the structural integrity of the tumor and/or blood vessels feeding the tumor. This can lead to an unobstructed dispersal of circulating cancer cells into the bloodstream (Ben-Eliyahu 2003; Yamaguchi 2000; Da Costa 1998; Shakhar 2003).This surgery-induced “alternate route” can greatly simplify the path to metastasis due to the release of vast quantities of tumor cells.

To illustrate, a study published in the British Journal of Cancer in 2001 compared the survival of women with breast cancer who had their tumors removed surgically, to the survival of women with breast cancer who did not have surgery. As expected, the data revealed that the surgery group had a spike in their risk of death at eight years that was not evident in the non-surgery group (Demicheli 2001). In their interpretation of the results, the authors of the study stated: “A reasonable hypothesis to explain the observed patterns of the hazard functions [risk of cancer death] is to assume that…primary tumor removal may result in sudden acceleration of metastatic process…”

Given these findings, a worthwhile strategy for scientists to protect against the increased risk of metastasis would be to examine all of the mechanisms by which surgery promotes metastasis, and then create a comprehensive plan that counteracts each and every one of them. This is preferrred as opposed to the current status quo, or even more radical surgery.

Preventing Surgery-Induced Immune Suppression

The immune system is essential in combating cancer. Natural killer (NK) cells are a type of white blood cell which seek out and destroys cancer cells. Research has shown that NK cells can spontaneously recognize and kill a variety of cancer cells (Herberman 1981).

In another study, preoperative NK cell activity in colon cancer patients was a better predictor of survival than the actual stage of the cancer itself (Koda 1997). The patients with reduced NK cell activity before surgery had a 350% increased risk of metastasis during the following 31 months.

In a study examining NK cell activity in women shortly after surgery for breast cancer, it was reported that low levels of NK cell activity were associated with an increased risk of death from breast cancer. (Mccoy 2000)

Impact Of Surgery On Immune Function

The first line of defense against malignancy is our natural killer cells (NK). Young individuals have high levels of functional natural killer immune cells, but this declines with aging.

Natural killer cells originate in the bone marrow (like other immune cells) and go through a maturation process that enables them to participate in early control of microbial infections as well as the detection and destruction of cancers.

The likelihood of surgery-induced metastasis requires the immune system to be highly active and vigilant in seeking out and destroying renegade cancer cells during the perioperative period (the time immediately before, during, and after surgery). Numerous studies have documented that cancer surgery results in a substantial reduction in NK cell activity (Da Costa 1998; Shakhar 2003; McCulloch 1993; Rosenne 2007; Welden 2009; Hogan 2011). In an investigation, NK cell activity in women having surgery for breast cancer was reduced by over 50% on the first day after surgery (McCulloch 1993). A group of renowned researchers stated that “we therefore believe that shortly after surgery, even transitory immune dysfunction might permit neoplasms [cancer] to enter the next stage of development and eventually form sizable metastases.” (Shakhar 2003).

The surgical procedure itself reduces NK activity. In other words, NK cell activity becomes impaired when it is most needed to fight metastasis. Surgical resection of solid tumors provides a major opportunity for metastasis.(Ben-Eliyahu 1999; Welden 2009; Hogan 2011) Surgery has been shown to suppress NK cell activity and elicit an abrupt and marked decrease in NK cell cytotoxicity that was detectable within only hours of surgical resection. (Pollock 1992) It also increased experimental metastasis to the lungs (Ben-Eliyahu 1999) of rats intravenously injected with tumor cells. Moreover, human studies have demonstrated that surgery suppresses NK cell activity for as long as 7 days, and preoperative NK cell activity values may not return for up to 2 weeks. (Yadavalli 2005; Koda 1997; Hogan 2011)

Our experience suggests that the mechanism underlying the phenomenon of surgery-induced impairment of NK cell activity, is that surgery itself exerts a toxic effect on NK cells. For example, Pollack and Lotzova (Pollock 1992) demonstrated that NK activity was diminished both in total rate and quantity of attacks during the post operative period. (Hogan 2011 ) Other surgical mechanisms of suppression suggest a multifactorial impairment of perioperative NK cell cytotoxicity. Erythroblasts generated at the time of surgery may compete for tumor target binding sites and thus block NK cytolytic mechanisms.

Taken together, these data support the following conclusions. First, an association between NK cell activity and metastasis has been shown in both animals and humans. Animal models have provided causal evidence that both experimental and spontaneous tumor metastasis depend on NK cell activity. Human studies completely support this relationship. Second, surgery-induced suppression of NK cell activity has been shown in both animals and humans. Hence, one can logically conclude that surgery-induced suppression of NK cell activity increases the risk of metastatic cancer.

With that said, if surgery has been elected, the perioperative period presents a window of opportunity to actively strengthen immune function by enhancing NK cell activity. Fortunately, numerous dietary supplements, most notably Dr. Farrah’s Boston-C, are known to significantly enhance NK cell activity.

Other nutraceuticals that have been documented to increase NK cell activity are garlic, glutamine, and IP6 (inositol hexaphosphate), (Ishikawa 2006; Baten 1989; Klimberg 2005; Matsui 2002). One experiment in mice with breast cancer found that glutamine supplementation resulted in a 40% decrease in tumor growth paired with a 2.5-fold increase in NK cell activity (Klimberg 2005).

Scientists in Germany explored the effects of mistletoe extract on NK cell activity in 62 patients undergoing surgery for colon cancer. The participants were randomized to receive either an intravenous infusion of mistletoe extract immediately before general anesthesia or general anesthesia alone. Measurements of NK cell activity were taken before and 24 hours after surgery. The group receiving anesthesia alone experienced a 44% reduction in NK cell activity 24 hours after surgery. The scientists reported that the group receiving mistletoe did not experience a significant decrease in NK cell activity after surgery. They went on to conclude that “perioperative infusion of mistletoe extracts can prevent a suppression of NK cell activity in cancer patients” (Schink 2007).

In a human trial of 30 patients undergoing surgical intervention for malignant obstructive jaundice, oral pretreatment with Dr. Farrah’s Boston-C (1000 ml/day) prevented septicemia (a life-threatening infection of the blood), normalized debris removal and killing capacity of the immune system’s white blood cells, and resulted in a postoperative survival rate of 92.4% in the treatment group versus 40% in the control group. Researchers concluded that strengthening of the immune system by consuming Dr. Farrah’s Boston-C may be responsible for considerable improvement in post-surgical outcome.

In laboratory studies, Dr. Farrah’s Boston-C was found to powerfully activate different types of lymphocytes, which are important immune factors. Researchers have found that it increased NK cell activity by 331%, T-cell activity by 102%, and B-cell activity by 39%, all of which demonstrate significantly increased immune activity. These observations have prompted numerous researchers to categorize Dr. Farrah’s Boston-C as “exhibiting remarkable immune stimulating properties”.

Cancer Surgery, Angiogenesis, and Metastasis

Angiogenesis (the formation of new blood vessels) is a normal and necessary process for childhood growth and development as well as wound healing. Unfortunately, cancers use this otherwise normal process in order to increase blood supply to the tumor. Because tumors cannot grow beyond the size of a pinhead (i.e., 1-2mm) without expanding their blood supply, the formation of new blood vessels supplying the tumor is a requirement for successful metastasis (Ribatti 2009; Rege 2005).

The primary tumor produces anti-angiogenic factors which serve to limit the growth of metastatic cancer elsewhere in the body (Baum 2005; Folkman 2003; Pinsolle 2000; Raymond 1998) by inhibiting the formation of new blood vessels to potential sites of metastasis. This ensures that a primary tumor can, at least for a time, maintain a competitive advantage for resources. Unfortunately, the surgical removal of the primary cancer also results in the removal of these anti-angiogenic factors, and the growth of metastasis is no longer inhibited. With these restrictions lifted, it is now easier for small sites of metastatic cancer to attract new blood vessels that promote their growth (Goldfarb 2006-2007). Indeed, these concerns were voiced by researchers who declared that “removal of the primary tumor might eliminate a safeguard against angiogenesis and thus awaken dormant micrometastasis [small sites of metastatic cancer]” (Shakhar 2003).

As it turns out, the surgery causes another angiogenic effect. After surgery, levels of vascular endothelial growth factor (VEGF) (factors that increase angiogenesis) are significantly elevated. This can result in an increased formation of new blood vessels supplying areas of metastatic cancer. A group of scientists asserted that “after surgery, the angiogenic balance of pro- and antiangiogenic factors is shifted in favor of angiogenesis to facilitate wound healing. Especially levels of vascular endothelial growth factor (VEGF) are persistently elevated. This may not only benefit tumor recurrence and the formation of metastatic disease, but also result in activation of dormant micrometastases” (van der Bij 2009).

In one experiment, EGCG, the active constituent of green tea, was administered to mice with stomach cancer. EGCG reduced the tumor mass by 60% and the concentration of blood vessels feeding the tumor by 38%. In addition, EGCG decreased the expression of VEGF in cancer cells by 80%. The authors of the study concluded that “EGCG inhibits the growth of gastric cancer by reducing VEGF production and angiogenesis, and is a promising candidate for anti-angiogenic treatment of gastric cancer” (Zhu 2007).

In a survey of curcumin’s anti-angiogenic effects, researchers noted that “Curcumin is a direct inhibitor of angiogenesis and also downregulates various proangiogenic proteins like vascular endothelial growth factor.” Additionally, they illustrated that “cell adhesion molecules are upregulated in active angiogenesis and curcumin can block this effect, adding further dimensions to curcumin’s antiangiogenic effect.” In conclusion, they commented that “Curcumin’s effect on the overall process of angiogenesis compounds its enormous potential as an antiangiogenic drug” (Bhandarkar 2007).

Surgical Anesthesia Can Influence Metastasis

The traditional protocol for anesthesia use is general anesthesia during surgery followed by intravenous morphine (for pain control) after surgery. However, this is not the optimal approach for preventing surgery-induced metastasis. At a time when immune function is already suppressed, morphine further weakens the immune system by diminishing NK cell activity (Vallejo 2004; Welden 2009) . Surgical anesthesia has also been shown to weaken NK cell activity (Melamed 2003). One study found that morphine increased angiogenesis and stimulated the growth of breast cancer in mice. The researchers concluded that “these results indicate that clinical use of morphine could potentially be harmful in patients with angiogenesis-dependent cancers” (Gupta 2002).

Given the inherent problems associated with the use of morphine and anesthesia, we feel that surgery should only be considered in immediate life threatening situations.

Numerous researchers have explored other approaches to surgical anesthesia and pain control. One approach is the use of conventional general anesthesia combined with regional anesthesia (anesthesia that affects a specific part of the body). The benefits achieved with this approach are two-fold –1) the use of regional anesthesia reduces the amount of general anesthesia required during surgery, and 2) it decreasing the amount of morphine needed after surgery for pain control (Goldfarb 2006-2007).

In one experiment, mice with cancer received surgery with either general anesthesia alone or combined with regional anesthesia. The scientists reported that the addition of regional anesthesia “markedly attenuates the promotion of metastasis by surgery.” Regional anesthesia reduced 70% of the metastasis-promoting effects of general anesthesia alone (Bar-Yosef 2001).

In another study, doctors compared NK cell activity in patients receiving general or regional anesthesia for abdominal surgery. NK cell activity dropped substantially in the general anesthesia group, while it was preserved at pre-operative levels in the group receiving regional anesthesia (Koltun 1996). In a pioneering study, 50 women having breast cancer surgery with general and regional anesthesia were compared to 79 women having breast cancer surgery and receiving general anesthesia followed by morphine. The type of regional anesthesia used was called a paravertebral block, which involves the injection of a local anesthetic around the spinal nerves between the vertebral bones of the spine. After nearly three years, dramatic differences were noted between the two groups. Only 6% of patients who received regional anesthesia experienced a metastatic recurrence compared to 24% in the group that did not receive regional anesthesia. In other words, women who received regional and general anesthesia had a 75% decreased risk for metastatic cancer. These findings led researchers to proclaim that regional anesthesia for breast cancer surgery “markedly reduces the risk of recurrence of metastasis during the initial years following surgery” (Goldfarb 2006-2007).

In yet another study, surgeons concluded that regional anesthesia “can be used to perform major operations for breast cancer with minimal complications. Most importantly, by reducing nausea, vomiting, and surgical pain, paravertebral block [regional anesthesia] markedly improves the quality of operative recovery for patients who are treated for breast cancer“ (Coveney 1998).

A group of researchers announced that “as regional techniques [anesthesia] are easy to implement, inexpensive, and do not pose a threat greater than general anesthesia, it would be easy for anesthesiologists to implement them, thus reducing the risk of disease recurrence and metastasis” (Goldfarb 2006-2007).

Those requiring medication for pain control after surgery can consider asking their doctor for tramadol instead of morphine. Unlike morphine, tramadol does not suppress immune function (Liu 2006). On the contrary, tramadol has been shown to stimulate NK cell activity (Boland et al. 2014).

Less Invasive Surgery Reduces Risk of Metastasis

Surgery places an enormous physical stress upon the body. There is considerable scientific evidence supporting the belief that less invasive surgeries, and therefore less traumatic, pose a decreased risk of metastasis. Laparoscopic surgery, performed by making a small incision in the abdomen, is one type of minimally invasive surgery.

In a study comparing laparoscopic to open surgery in colon cancer patients receiving a partial colectomy (removal of the colon), the laparoscopic group had a 61% decreased risk of cancer recurrence coupled with a 62% decreased risk of death from colon cancer. The surgeons concluded that laparoscopic colectomy is more effective than open colectomy for treatment of colon cancer (Lacy 2002). A long-term (median time ~8 years) follow-up of these patients reported a 56% decreased risk of death from colon cancer following laparoscopic surgery as compared to traditional open surgery (Lacy 2008).

Minimally invasive surgery has produced substantial improvements in survival rates for lung cancer patients as opposed to open chest surgeries. Video-assisted thoracoscopic surgery (VATS) was compared to traditional open surgery for removing lung tumors (lobectomy). The five-year survival rate from lung cancer was 97% in the VATS group compared to 79% in the open surgery group (Kaseda 2000).

A group of surgeons commented that minimally invasive surgery for lung cancer “can be performed safely with proven advantages over conventional thoracotomy [chest surgery] for lobectomy: smaller incisions, decreased postoperative pain, decreased blood loss, better preservation of pulmonary function, and earlier return to normal activities. The evidence in the literature is mounting that VATS may offer reduced rates of complications and better survival” (Mahtabifard 2007).

Surgical Inflammation and Metastasis

Cancer surgery causes an increased production of inflammatory chemicals such as interleukin-1 and interleukin-6 (Baigrie 1992; Wu 2003; Volk 2003). These chemicals are known to increase the activity of cyclooxygenase-2 (COX-2). A highly potent inflammatory enzyme, COX-2 plays a pivotal role in promoting cancer growth and metastasis by stimulating the formation of new blood vessels feeding the tumor (Tsujii 1998; Chu 2003). It also increases cancer cell adhesion to the blood vessel walls (Kakiuchi 2002), thereby enhancing the ability of cancer cells to metastasize.

This was evident in an article which reported levels of COX-2 in pancreatic cancer cells to be 60 times greater than in normal pancreatic cells (Tucker 1999). Levels of COX-2 were 150 times higher in cancer cells from individuals with head and neck cancers compared to normal tissue from healthy volunteers (Chan 1999). This was further supported when

Two hundred eighty-eight individuals undergoing surgery for colon cancer had their tumors examined for the presence of COX-2. With other factors being controlled, the group whose cancers tested positive for the presence of COX-2 had a 300+% greater risk of death compared to the group whose cancers did not express COX-2 (Soumaoro 2004). A subsequent study in lung cancer patients found that those with high tumor levels of COX-2 had a median survival rate of 15 months compared to 40 months in those with low levels (Yuan 2005).

Given these findings, researchers began investigating the anti-cancer effects of COX-2 inhibitors. Although initially used for inflammatory conditions (i.e., arthritis), COX-2 inhibitors have been shown to possess powerful anti-cancer benefits.

In a groundbreaking study, the incidence of bone metastases in breast cancer patients receiving COX-2 inhibitors for at least six months (following the initial diagnosis of breast cancer) was compared to the incidence in breast cancer patients not taking a COX-2 inhibitor. Those taking a COX-2 inhibitor were almost 80% less likely to develop bone metastases than those not taking a COX-2 inhibitor (Tester 2012).

Scientists created an experimentally-induced increase in COX-2 activity in human breast cells, which was completely prevented by resveratrol. Resveratol blocked the production of COX-2 within the cell, as well as blocking COX-2 enzyme activity (Subbaramaiah 1998).

The science is clear, and it demonstrates that after surgery, even a short period of immune dysfunction can permit cancer to start the next stage of development and form metastasis’. After surgery the body is more focused on healing the wound and detoxing the anesthetic, than killing the cancer and so the natural killer cell concentration, activity, and cytotoxicity is decreased, just when they are needed the most. Therefore, we feel that surgery should only be considered in immediate life threatening situations, and even then, should be carefully evaluated.

Boland et al. Effects of opioids on immunologic parameters that are relevant to anti-tumour immune potential in patients with cancer: a systematic literature review. British Journal of Cancer (2014) 111, 866–873

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